Hypercapnia, the elevation of carbon dioxide (CO2) levels in blood and tissues, is common in chronic obstructive pulmonary disease (COPD) and acute respiratory failure. Importantly, hypercapnia is a predictor of increased mortality in both COPD and community-acquired pneumonia. However, it is not known whether hypercapnia is merely a marker of severe lung disease, or plays a causative role in adverse clinical outcomes. The applicant's preliminary studies show that hypercapnia suppresses macrophage synthesis of multiple cytokines regulated by NF-:B p65/Rel A that are critical for host defense, and also inhibits phagocytosis. Furthermore, she has shown that hypercapnia increases mortality in a mouse model of pneumonia caused by Pseudomonas aeruginosa. These findings suggest that hypercapnia may increase susceptibility to or worsen outcomes of pulmonary infection in patients with advanced lung disease. In the mouse pneumonia studies, hypercapnia inhibited clearance of P. aeruginosa from the lungs, despite robust pulmonary neutrophil influx. Based on these observations, the applicant hypothesizes that hypercapnia impairs lung host defense and increases the mortality of P. aeruginosa pneumonia by inhibiting activation of NF-:B, phagocytosis and killing of bacteria in the neutrophil. This hypothesis will be examined in two specific aims, focused on determining whether hypercapnia inhibits (1) NF-:B activation and (2) phagocytosis and killing of bacteria in mouse and human neutrophils in vitro and in neutrophils recruited to the lungs of mice with P. aeruginosa pneumonia. These studies will provide new information about how hypercapnia alters neutrophil function and suppresses host defense in the lung, a clinically important but previously uninvestigated problem. Ultimately, this avenue of investigation should lead to new strategies for limiting susceptibility to pulmonary infection in patients with hypercapnic lung disease. In addition, the proposed investigation is the cornerstone of an advanced research training experience for applicant, Dr. Khalilah L. Gates, as she prepares for a physician-scientist career in lung biology investigation. PUBLIC HEALTH RELEVANCE: Patients with chronic lung diseases such as chronic obstructive pulmonary disease (COPD) often have elevated levels of carbon dioxide make patients more susceptible to infections and frequently have recurrent infections. Research has shown that elevated levels of carbon dioxide may make it more difficult for patients to recover from infections. If this relationship is correct, there would be more options to improve prevention and treatment of infections in these patients.